Celiac crisis, transient hypertransaminasemia and positive smooth muscle antibodies (SMA): A celiac disease case report

Abstract Celiac crisis (CC) is a rare complication of celiac disease (CD), usually observed in younger children with unrecognized CD or poor compliance with a gluten‐free diet (GFD). We present a case of celiac crisis in a 3‐year‐old girl who was recently diagnosed with celiac disease. She was referred to our clinic with anasarca, tetany, and severe malnutrition, with hypokalemia, hypocalcemia, hypomagnesemia, and hypoalbuminemia. During hospitalization, she presented hypertransaminasemia with positive anti‐actin smooth muscle antibodies (SMA). Abdominal ultrasound and liver biopsy were normal, excluding autoimmune hepatitis. Liver involvement is a common CD extraintestinal manifestation and cryptogenic form is the most common. SMA positivity could be associated with a systemic immune cross reaction. Our patient normalized liver values after 2 months of GFD.


| INTRODUCTION
Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten in genetically susceptible individuals and is characterized by a variable combination of clinical manifestations, CD-specific antibodies, and enteropathy with subsequent nutritional malabsorption. 1 In Italy, the prevalence of CD in children is 1.65%. 2 Celiac crisis (CC) is a rare complication of CD, is most frequent in early childhood, and is often triggered by intestinal infectious diseases. 3CC could be a complication of unrecognized CD or a consequence of noncompliance with the recommended gluten-free diet (GFD).Liver involvement is a common manifestation of CD: isolated hypertransaminasemia is frequent, but in some cases, cryptogenic cirrhosis and liver transplant are reported. 4We present a case of a 3-year-old girl with CC and suspected autoimmune hepatitis in a recent CD diagnosis.

| MATERIALS AND METHODS
We performed a literature search of other similar cases.

| CASE PRESENTATION
We present the case of a 3-year-old girl admitted to our emergency department because of CC.She had a 1-month history of diarrhea and asthenia, so a few days before, she performed stool microbiological tests resulted negative and blood tests that resulted positive for IgA anti-tissue transglutaminase antibodies (anti-TG2) (8200 UA/mL, cut-off <7.0 U/mL) and IgA antiendomysial (EMA) antibodies at high titers in a second blood sample.She presented high level values at the calprotectin test.Therefore, she was diagnosed with CD according to the recent European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), with no-biopsy approach, and she started a GFD. 1 A few days later, she was referred to our clinic with anasarca, tetany and weight loss.The first blood tests revealed neutropenia (neutrophil count: 150/mmc) and severe malnutrition with typical signs of CC such as hypokalemia, hypocalcemia, hypomagnesemia and hypoalbuminemia (see Table 1).She performed an infusion to correct electrolyte imbalance.Autoimmune thyroiditis, autoimmune neutropenia and immunological deficits were excluded: lymphocyte subpopulations and IgG, IgM and IgA immunoglobulins were normal.A few days after hospitalization, she presented a progressive hypertransaminasemia (Figure 1) with maximum values of aspartate aminotransferase (AST) 111 U/L and alanine transaminase (ALT) 221 U/L, with normal gamma-glutamyl transferase (GGT) value.She performed an abdominal ultrasound that did not show hepatosplenomegaly or hepatic injuries.Smooth muscle antibodies (SMA) resulted positive (title 1:320, vessels-glomerulartubular (VGT) immunofluorescence pattern, anti-actin pattern) and, in the suspicion of autoimmune hepatitis (AIH), a liver biopsy was performed.The results of the biopsy allowed us to exclude liver injuries and autoimmune hepatitis.Transaminase values normalized 2 months after starting GFD (Table 1).

| DISCUSSION
Our patient presented with CC with severe nutritional deficiencies, malnutrition, and hypertransaminasemia related to CD.Our patient also met moderate-severe criteria for refeeding syndrome (−2.9 z-score, weight loss, electrolyte imbalance, etc.) according to the American Society for Parenteral and Enteral Nutrition (ASPEN), 5 which may be associated with CC, as reported in the literature. 6Liver involvement is a common extraintestinal manifestation from mild hepatic injury to severe liver disease.Liver can be involved in two main forms: cryptogenic and autoimmune disease.The first type is frequent.In a recent meta-analysis, Sainsbury et al. 7 estimated the prevalence of CD in adults with cryptogenic hypertransaminasemia and the prevalence of hypertransaminasemia in patients with a new CD diagnosis.The combined proportion with positive celiac serology and biopsy-proven CD in unexplained hypertransaminasemia were 6% and 4%, respectively.Approximately one-third of patients newly diagnosed with CD had hypertransaminasemia. 7 Iorio et al. investigated 425 children with isolated hypertransaminasemia. 8 Three of 166 patients (1.8%) with persistent hypertransaminasemia were identified as having CD.This is about two times the risk of CD in the general population.So, a routine laboratory screening for CD in patients with unexplained hypertransaminasemia can be useful in diagnosing CD in the absence of other symptoms.Even in children hypertransaminasemia may represent the only manifestation of CD, in fact about 40% of children had isolated hypertransaminasemia during diagnostic analysis for suspected CD.In our case, biochemical liver tests normalized after 2 months of GFD.The pathogenesis of the hypertransaminasemia and liver damage in CD remains currently unknown.AIH is less frequently diagnosed.Other rare types of liver damage in CD are primary sclerosing cholangitis and fatty liver disease.In our case, we perform a liver biopsy due to positive serology SMA and to exclude AIH.Liver biopsy was normal and transaminase values normalized after 2 months of GFD.SMA antibodies are a heterogenous group of antibodies directed against cytoskeleton components, found in liver diseases, viral infections, autoimmune pathologies and tumor cells. 9Infectious diseases were not further investigated considering the recent diagnosis of CD and the absence of symptoms and laboratory tests suggestive of viral infection, such as white blood

What is Known
• Celiac disease (CD) is a commonly diagnosed pediatric disorder that may present with celiac crisis (CC), a relatively uncommon occurrence.
• The onset of CD may also be associated with liver injuries and, occasionally, autoimmune hepatitis (AIH).AIH is suspected through the detection of specific antibodies, smooth muscle antibodies (SMA), and hypertransaminasemia.

What is New
• In our case, CC demonstrated transient hepatic injury, as indicated by a transient hypertransaminasemia, followed by rapid normalization.• CD triggers immune system activation, leading to the development of specific antibodies typically associated with liver disease.In certain instances, as in our patient, positive F-actin SMA antibodies in CD may result from a cross-reaction mechanism.Alternatively, it may be linked to villous intestinal atrophy.

Translational impact
• Given the prevalence of CD, understanding its potential rare complications is crucial.• In cases of hypertransaminasemia and positive SMA antibodies, particularly of the antiactin type, consideration for undiagnosed CD is recommended.
T A B L E 1 Blood tests showed severe acute malnutrition (electrolytes disorders, folate and vitamin D deficiency, prolonged INR caused by vitamin K deficiency, etc.), liver injuries and transient hypertransaminasemia.

Unit of measurement
Values at admission time  cells and lymphocytes in range, negative C-reactive protein and erythrocyte sedimentation rate both 2 weeks before the onset of CC and during the hospitalization.Bottazzo et al. described the distribution of specific SMA variants in liver diseases (V-G-T: vessels, glomeruli, tubuli) and the association between SMA T/G antibodies at higher titers (greater than 1:80) and AIH. 10 Anti-actin SMA antibodies are most specific for type 1 AIH but they are also described in CD (in particular F-actin pattern) and appear to be related to the presence of intestinal villus atrophy and to more severe clinical CD outcome, so Clemente et al.
suggested that it could be used as a marker of severe intestinal atrophy. 11Granito et al. stressed the possibility of cross-linking between the actin filaments of the cytoskeleton with tTG, as actin is a good substrate of it.Indeed, the cross-linking could explain a hypothetical mechanism of secondary autoimmune phenomena related to CD. 12 Our patient did not perform an intestinal biopsy to evaluate villous atrophy but the onset with CC and the presence of actin IgA and SMA VGT at high title raise suspicion of important intestinal injuries.

| CONCLUSION
CC is a rare onset of CD, and it could be triggered by an immune activation caused by a general immune stimulus (infectious diseases, trauma, or untreated CD as in our patient).Our girl presented typical CC symptoms but also hypertransaminasemia and specific liver diseases antibodies.We performed transaminase monitoring and liver biopsy on suspicion of AIH in consideration of the clinic and blood tests.The results showed that AIH was not confirmed, so SMA positivity could be associated with an immune cross reaction.Although more and more detailed techniques, such as specific methods of indirect immunofluorescence, western blot and ELISA tests, are being used to look for the most specific antibodies to every different type of liver disease, it is still not possible to rely on serology to rule out AIH, making it necessary to perform a liver biopsy.